PMID- 20685651
OWN - NLM
STAT- MEDLINE
DCOM- 20101116
LR  - 20240322
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 44
DP  - 2010 Oct 29
TI  - Ras homolog enriched in brain (Rheb) enhances apoptotic signaling.
PG  - 33979-91
LID - 10.1074/jbc.M109.095968 [doi]
AB  - Rheb is a homolog of Ras GTPase that regulates cell growth, proliferation, and 
      regeneration via mammalian target of rapamycin (mTOR). Because of the well 
      established potential of activated Ras to promote survival, we sought to 
      investigate the ability of Rheb signaling to phenocopy Ras. We found that 
      overexpression of lipid-anchored Rheb enhanced the apoptotic effects induced by 
      UV light, TNFalpha, or tunicamycin in an mTOR complex 1 (mTORC1)-dependent manner. 
      Knocking down endogenous Rheb or applying rapamycin led to partial protection, 
      identifying Rheb as a mediator of cell death. Ras and c-Raf kinase opposed the 
      apoptotic effects induced by UV light or TNFalpha but did not prevent Rheb-mediated 
      apoptosis. To gain structural insight into the signaling mechanisms, we 
      determined the structure of Rheb-GDP by NMR. The complex adopts the typical 
      canonical fold of RasGTPases and displays the characteristic GDP-dependent 
      picosecond to nanosecond backbone dynamics of the switch I and switch II regions. 
      NMR revealed Ras effector-like binding of activated Rheb to the c-Raf-Ras-binding 
      domain (RBD), but the affinity was 1000-fold lower than the Ras/RBD interaction, 
      suggesting a lack of functional interaction. shRNA-mediated knockdown of 
      apoptosis signal-regulating kinase 1 (ASK-1) strongly reduced UV or TNFalpha-induced 
      apoptosis and suppressed enhancement by Rheb overexpression. In conclusion, 
      Rheb-mTOR activation not only promotes normal cell growth but also enhances 
      apoptosis in response to diverse toxic stimuli via an ASK-1-mediated mechanism. 
      Pharmacological regulation of the Rheb/mTORC1 pathway using rapamycin should take 
      the presence of cellular stress into consideration, as this may have clinical 
      implications.
FAU - Karassek, Sascha
AU  - Karassek S
AD  - Department of Molecular Neurobiochemistry, Faculty of Chemistry and Biochemistry, 
      Ruhr University of Bochum, 44780 Bochum, Germany.
FAU - Berghaus, Carsten
AU  - Berghaus C
FAU - Schwarten, Melanie
AU  - Schwarten M
FAU - Goemans, Christoph G
AU  - Goemans CG
FAU - Ohse, Nadine
AU  - Ohse N
FAU - Kock, Gerd
AU  - Kock G
FAU - Jockers, Katharina
AU  - Jockers K
FAU - Neumann, Sebastian
AU  - Neumann S
FAU - Gottfried, Sebastian
AU  - Gottfried S
FAU - Herrmann, Christian
AU  - Herrmann C
FAU - Heumann, Rolf
AU  - Heumann R
FAU - Stoll, Raphael
AU  - Stoll R
LA  - eng
SI  - PDB/2L0X
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100804
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neuropeptides)
RN  - 0 (Proteins)
RN  - 0 (RHEB protein, human)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Amino Acid Sequence
MH  - *Apoptosis
MH  - Endoplasmic Reticulum/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Magnetic Resonance Spectroscopy/methods
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Molecular Conformation
MH  - Molecular Sequence Data
MH  - Monomeric GTP-Binding Proteins/*metabolism
MH  - Multiprotein Complexes
MH  - Neurons/metabolism
MH  - Neuropeptides/*metabolism
MH  - Oxidative Stress
MH  - Proteins
MH  - Ras Homolog Enriched in Brain Protein
MH  - Sequence Homology, Amino Acid
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/metabolism
PMC - PMC2962498
EDAT- 2010/08/06 06:00
MHDA- 2010/11/17 06:00
PMCR- 2010/08/04
CRDT- 2010/08/06 06:00
PHST- 2010/08/06 06:00 [entrez]
PHST- 2010/08/06 06:00 [pubmed]
PHST- 2010/11/17 06:00 [medline]
PHST- 2010/08/04 00:00 [pmc-release]
AID - S0021-9258(20)47111-X [pii]
AID - M109.095968 [pii]
AID - 10.1074/jbc.M109.095968 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Oct 29;285(44):33979-91. doi: 10.1074/jbc.M109.095968. Epub 
      2010 Aug 4.